Combination of detoxified pneumolysin derivative ΔA146Ply and berbamine as a treatment approach for breast cancer

Abstract Increasing evidences demonstrate that microorganisms and their products can modulate host responses to cancer therapies and contribute to tumor shrinkage via various mechanisms including intracellular signaling pathways modulation and immunomodulation. Detoxified pneumolysin derivative ΔA146Ply is a pneumolysin mutant lacking hemolytic activity. To determine the antitumor activity of ΔA146Ply, the combination of ΔA146Ply and berbamine, a well-established antitumor agent, was used for breast cancer therapy, especially for triple negative breast cancer. The efficacy of the combination therapy was evaluated in vitro using four breast cancer cell lines and in vivo using a synergistic mouse tumor model. We demonstrated that in vitro the combination therapy significantly inhibited cancer cell proliferation, promoted cancer cell apoptosis, caused cancer cell cycle arrest, and suppressed cancer cell migration and invasion. In vivo the combination therapy significantly suppressed tumor growth and prolonged the median survival time of tumor-bearing mice partially through inhibiting tumor cell proliferation, promoting tumor cell apoptosis, and activating systemic antitumor immune responses. The safety analysis demonstrated that the combination therapy showed no obvious liver and kidney toxicity to tumor-bearing mice. Our study provides a new treatment option for breast cancer and lays the experimental basis for the development of ΔA146Ply as an antitumor agent.